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Eloxatin

Eloxatin

BRANDED
For one ml of concentrate for an infusion solution of 10 ml of concentrate for an infusion solution of 50 mg of oxaliplatin & 20 ml of concentrate for an infusion solution of 100 mg oxaliplatin
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THERAPEUTIC INDICATIONS

Oxaliplatin in combination with 5-Fluorouracil (5-FU) and folinic acid (FA) is indicated for:

·   Adjuvant treatment of stage III (Duke’s C) colon cancer after complete resection of primary tumor.

·   Treatment of metastatic colorectal cancer.

 

POSOLOGY AND METHOD OF ADMINISTRATION

Dosage:

RESERVED FOR USE IN ADULTS:

Dosage

RESERVED FOR USE IN ADULTS.

The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m2 intravenously, repeated every 2 weeks for 12 cycle (6 months).

The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is

85 mg/m2 intravenously repeated every two weeks.

 

Dosage given should be adjusted according to tolerability. Oxaliplatin should always be administered before fluoropyrimidines.

Oxaliplatin is administered as a 2-6 hour intravenous infusion in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml.

Oxaliplatin was mainly use in combination with continuous infusion 5-Fluorouracil based regimens. For the two-weekly treatment schedule 5-Fluorouracil regimens combining bolus and continuous infusion were used.

 

Population as risk

- Patient with renal impairment:

Oxaliplatin has not been studied in patients with severe renal impairment.

In patients with moderate renal impairment, treatment may be initiated at the recommended dose. There is no need for dose adjustment with patients with mild renal dysfunction.

- Patient with Hepatic Insufficiency:

Oxaliplatin has not been studied in patients with severe hepatic impairment. No increase in oxaliplatin acute toxicities was observed in the subset of patients in abnormal liver function. During clinical development, no specific dose adjustment was made in patients presenting with abnormal liver functions.

- Elderly subjects:

No Increase in severe toxicities was observed when oxaliplatin was used as a single  agent  or  in  combination  with 5-fluorouracil(5-FU)  in  subject  over  the  age of 65. Consequently, no specific dose adjustment is required for elderly subjects.

 

Method of administration

Oxaliplatin is administered by intravenous infusion.

The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500 ml of 5% sucrose solution to give a concentration not less than 0.2 mg/ml must be infused either via central venous line or peripheral vein over 2-6 hours. Oxaliplatin infusion should always precede that of 5-Fluorouracil. In the event of extravasation, administration must be discontinued immediately.


Instruction for use

Oxaliplatin must be diluted prior to administration. Only the recommended diluent should be used to dilute the concentrate for solution for infusion (See “Instructions for  use  and  handling”).


CONTRAINDICATIONS

Oxaliplatin is contraindicated in patients who:

- Have a history of hypersensitivity to oxaliplatin.

- are breast feeding.

- Have  myelosuppression  (neutrophils   <  2x109/l  and/or   platelet  count  of < 100x109l)  before  the  first  cycle  treatment.

- Have sensory peripheral sensitive neuropathy with functional impairment prior to the first cycle of treatment

- have  severe  renal  insufficiency  (creatinine  clearance  <  30  ml/min)

 

 

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

 

For use in pregnant women see section 4.6 “Pregnancy and Lactation”. 

- Due to limited information on safety in patients with moderate renal impairment, administration should only be considered after suitable appraisal of the benefit/risk for the patient. In this case, renal function should be closely monitored and dose adjusted according to toxicity.

- Patients with a history of allergic reactions to platinum compounds should be the monitored for allergic symptoms. Allergic reaction can occur during any cycle. In case of symptoms of an anaphylactic-like reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin rechallenge is contra-indicated.

-  In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.

-  Neurological toxicity of oxaliplatin should be carefully monitored, especially if co- administered with other medications with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.

- For patients who develop acute laryngo-pharyngeal dysesthesia within or during the hours  following  the  two-hour  infusion,  the  next  oxaliplatin  infusion  should  be administered over six hours. To prevent such dysaesthesia, inform the patient to avoid exposure to cold and to avoid ingesting fresh/cold food or/and beverages during or within the hours following oxaliplatin administration.

- If neurological symptoms (paresthesia, dysesthesia) occur, the following recommended oxaliplatin dosage adjustment, based on the duration and severity of these symptoms, should be performed:

· If symptoms last for more than 7 days and are painful, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m² (treatment  of  metastatic) or to 75 mg/ml² (adjuvant  treatment)

· if paresthesia without functional impairment persists until the next cycle, the oxaliplatin dose should be reduced from 85 to 65 mg/m² (metastatic  treatment) or to 75 mg/m² (adjuvant  treatment)

· if paresthesia with functional impairment persists until the next cycle, oxaliplatin administration should be discontinued

· if symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may be considered.

-  Patient must be informed that the symptoms of sensory peripheral neurophathy may persist after the end of the treatment. Moderate Localized paraesthesia which may interfere with functional activities may persist for more than 3 years after the discontinuation of adjuvant treatment.

-  Signs and symptoms of Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.

-  Gastrointestinal toxicity which manifests as nausea and vomiting warrants prophylactic and/or therapeutic anti-emetic therapy.

-  Dehydration, paralytic ileus, intestinal obstruction, hypocalemia, metabolic acidosis and impairment of renal function may be caused by severe diarrhea and/or vomiting, particularly  when  oxaliplatin  is  used  in  combination  with  5-fluorouracil.

-  Cases of intestinal ischaemia, including fatal outcomes, have been reported with Oxaliplatin treatment. In case of intestinal ischaemia, Oxaliplatin treatment should be discontinued and appropriate measures initiated.

-  If haematological toxicity  occurs  (neutrophils  <  1.5x109/l  or  platelet  <  50x109/l), administration of the next cycle should be postponed until haematological values return to acceptable levels. A full blood count with cell differential should be performed prior to initiating oxaliplatin therapy and before each subsequent cycle.

-  Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis  and  neutropenia  after  oxaliplatin  and  5-fluorouracil  administration in order to contact their treating physician for appropriate management.

-  In the event of mucositis/stomatitis with or without neutropenia, the subsequent administration should be postponed until the mucositis/stomatitis has regressed to a grade less than or equal to 1 and/or neutrophil count ≥ 1.5x109/l.

-  For  oxaliplatin combined  with  5-fluorouracil (with  or  without  folinic  acid),  the  usual dose  adjustments for 5-fluorouracil  associated  toxicities  should  apply.

-  If severe/life-threatening (grade-4) diarrhoea, severe (grade-3-4) neutropenia (neutrophils  <1x109/l),  febrile  neutropenia  (fever  of  unknown  origin  without  clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 109/L, a single temperature of > 38.3°C or a sustained temperature of > 38°C for  more  than  one  hour),  or  severe (grade-3-4) thrombocytopenia  (platelets

<50x109/l) occur,  oxaliplatin  must  be  discontinued  until  improvement  or  resolution, in  addition  to  any  5-fluorouracil  dosage  reductions  required,  and  a  reduction  in  the dose of oxaliplatin from 85 to 65 mg/m² (metastatic treatment) or to 75 mg/m² (adjuvant  treatment).

-  Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with  oxaliplatin,  including  fatal  outcomes8  (see  section  11).  If  any  of  these  events occurs, oxaliplatin should be discontinued.

-  Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with Oxaliplatin treatment. If DIC is present, Oxaliplatin treatment should be discontinued and appropriate treatment should be administered.

-  In case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease.

-  In case of abnormal liver function test results or portal hypertension which does not obviously result from liver metastases, very rare cases of drug-induced hepatic vascular disorders should be considered.

-  QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade  de  Pointes,  which  can  be  fatal  (see  section  11).  Caution  should  be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment should be discontinued.

-  Rhabdomyolysis has been reported in patients treated with Oxaliplatin, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, Oxaliplatin treatment should be discontinued. If rhabdomyolysis is confirmed, appropriate measures should be taken. Caution is recommended if medicinal products associated with rhabdomyolysis are administered concomitantly with Oxaliplatin.

-  Oxaliplatin treatment can cause duodenal ulcer (DU) and potential complications, such as duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer, Oxaliplatin treatment should be discontinued and appropriate measures taken.

-  Do not use oxaliplatin intraperitoneally. Peritoneal hemorrhage may occur when Oxaliplatin  is  administered  by  intraperitoneal  route  (off-label  route  of  administration.

 

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

In patients who have received a single dose of 85 mg/m² of oxaliplatin, immediately prior  to  the  administration  of  5-fluorouracil,  no  charge  in  the  level  of  exposure  to 5-fluorouracil  has  been  observed.

In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.

Caution is advised when Oxaliplatin treatment is co-administered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored.

Caution is advised when Oxaliplatin treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis.

 

PREGNANCY AND LACTATION

No data are currently available concerning the safety of oxaliplatin in pregnant women. Based on pre-clinical findings, the use of oxaliplatin, is likely to be lethal and/or teratogenic to the foetus at the recommended therapeutic dose, and is therefore not recommended during pregnancy should only be considered once the patients has been clearly informed as to the risks to the foetus and her consent obtained.

Passage  into  breast  milk  has  not  been  studied.  Breast-feeding  is  contra-indicated during oxaliplatin with oxaliplatin.

 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No data available

 

UNDESIRABLE EFFECTS

The most common undesirable effects experienced during the combination of oxaliplatin with  5-fluorouracil/folinic acid (5-FU/FA) are gastrointestinal (diarrhea,  nausea, vomiting   and   mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose cumulative sensory peripheral neuropathy). These undesirable events have been generally more frequent and more severe with oxaliplatin in combination with 5-FU/FA than with 5-FU/FA alone.

The incidences shown in the table below were obtained during clinical studies on the treatment of metastases and on adjuvant treatment (which included 416 and 1108 patients, respectively, in this oxaliplatin + 5-FU/FA arm, repectively) and form post- marketing surveillance.

The frequencies shown in the table were defined using the following criteria: very common (>1/10), common (>100,  ≤1/10), uncommon (>1/1000,  ≤1/100), rare (>1/10000,  ≤1/1000) and very rare (≤1/10000), including isolated cases.


Further information is given after the table.

 

* see detailed section below

* * Special Warnings and Special Precautions for Use.


Haematological toxiticy


Digestive toxicity


Prophylaxis and/or treatment with patent antiemetic agents is indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypocalemia, metabolic acidosis and renal impairment may be caused by severe diarrhea and/or vomiting, particularly when  oxaliplatin  is  combined with  5-fluorouracil  (see  4.4  “Special  warnings  and precautions  for  use”).

 

Nervous system:

The dose limiting toxicity of oxaliplatin is neurological. This mainly involves sensory peripheral neurophaty characterized by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between cycles of treatment, increases with the number of cycles.

Depending on the duration of symptoms, the onset of pain and/or functional disorder requires dose adjustment or even treatment discontinuation (see 4.4 “Special warnings and  precautions  for  use”).


Such functional impairment, which includes difficulty in executing delicate movements, is a possible consequence of sensory damage. The risk of onset of persistent symptoms with a cumulated dose of 850 mg/m² (i.e. 10 cycles) is around 10%, and around 20% for a cumulated dose of 1020 mg/m² (i.e. 12 cycles).

In most cases, neurological symptoms improve or are totally resolved when treatment is discontinued.

Six months after treatment discontinuation in the adjuvant setting of colon cancer, 87% of patients had no or mild symptoms. After more than 3 years of follow-up, about 3% of patients presented with either persisting, localized paraesthesia of moderate intensity (2.3%) or paraesthesia that may interfere with functional activities (0.5%).

Acute  neurosensory  manifestations  have  been  reported  (see  5.3  “Preclinical  safety data”).  They  start  within  hours  of  administration  and  often  occur  on  exposure  to cold.

They are characterized by transient paraesthesia, dysaesthesia and hypoaesthesia, or as an acute syndrome of laryngopharyngeal dysaesthesia. This acute syndrome, the incidence of which is estimated between 1% and 2%, is characterized by subjective sensations of dysphagia or dyspnoea, without any objective sign of respiratory distress (no cyanosis or hypoxia) or by laryngospasm or bronchospasm (no stridor or wheezing); jaw spasm, abnormal tongue sensation, dysarthria and a feeling of chest pressure have also been observed.

Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible, even in the absence of treatment, prologation of the infusion during subsequent cycles helps to reduce the incidence of this syndrome  (see  4.4  “Special  warnings  and  precautions  for  use”).

Other neurological symptoms, such as dysarthria, loss of tendon reflex and Lhermitte’s sign were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

 

Post-marketing experience with frequency not known:

- Infections and infestations

Septic shock, including fatal outcomes

- Blood and lymphatic system disorders

Haemolytic uremic syndrome, autoimmune, pancytopenia, pancytopenia, secondary leukemia.

- Nervous system disorders:

Convulsion, ischemic and hemorrhagic cerebrovascular disorder

- Cardiac disorders:

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal

Acute coronary syndrome, including myocardial infarction, coronary arteriospasm and angina pectoris have been described in patients treated with oxaliplatin in combination with 5-FU and bevacizumab

- Respiratory, thoracic and mediastinal disorders

Laryngospasm, pneumonia and bronchopneumonia, including fatal outcomes.

- Gastrointestinal disorders

· intestinal ischaemia, including fatal outcomes.

· duodenal ulcer,  and  complications,   such  as  duodenal ulcer haemorrhage or perforation, which can be fatal.

· esophagitis

- Musculoskeletal and connective tissue disorders

rhabdomyolysis, including fatal outcomes

 

Immune system disorders

delayed hypersensitivity.

 

Skin and subcutaneous tissue disorders

hypersensitivity vasculitis.

 

Allergic reactions


OVERDOSE

There is no known antidote to oxaliplatin. In the event of overdose, exacerbation of undesirable effects can be expected. Monitoring of haematological parameters must be initiated, together with symptomatic treatment of other toxicities.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

CYTOTOXIC Agent

(Other antineoplastic agent) ATC code : L01XA 03

Oxaliplatin is an antineoplastic agent belonging to a new class of platinum compounds in  which  the  platinum  atom  is  complexed  with  1,2-diaminocyclohexane  (“DACH”) and an oxalate group.

Oxaliplatin    is    a    single    enantiomer,    (cis-[(1R,2R)-1,1-cyclohexanediamine-

N,N’]oxalate(20)-0,0’)platinum.

Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour activity in a variety of tumour model systems, including human colorectal cancer models.

Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin-resistant cell lines.

Synergistic  cytotoxic  activity  with  5-fluorouracil  has  been  demonstrated  both  In  vitro and in vivo. Studies on the mechanism of action, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both intra and inter-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.


In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m² repeated  every  two  weeks)  in  combination  with  5-fluorouracil/folinic  acid  has  been reported in three clinical studies:

· In  first-line  treatment,  the  2-am  comparative  phase  III  EFC2962  study  randomized

420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210).

· In pretreated patients, the comparative three arms phase III study EFC4584 randomised  821  patients  refractory  to  an  irinotecan  (CPT-11)  +  5-FU/FA combination either to 5-FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275),  or  combination  of  oxaliplatin  with  5-FU/FA  (FOLFOX4,  N=271).

· Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).

 

The two randomized clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PPS)/time to progression (TTP) as compared to treatment with 5-FU/FA alone. In EFC4584 performed in between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance.

NA : not applicable


NA : not applicable


NA : not applicable


In pretreated patients (EFC4584), who were symptomatic at baseline, a higher proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant improvement of their disease-related symptoms compared to those treated with 5- FU/FA  alone  (27.7%  vs  14.6%  p  =  0.0033).

In non-pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found for any of the quality of life dimensions.

However, the quality of life scores were generally better in the control arm for measurement of global health status and pain and worse in the oxaliplatin arm for nausea and working.

In  the  adjuvant  setting,  the  MOSAIC  comparative  phase  III  study  (EFC3313) randomized 2246 patients (899 stage II/Duke’s B2 and 1347 stage III/Duke’s C) further to complete resection of the primary tumour of colon cancer either to 5- FU/FA alone (LV5FU2, N=1123 (B2/C = 448/675) or to combination of oxaliplatin and  5-FU/FA  (FOLFOX4,  N=1123  (B2/C)  =  451/672).


EFC3313: Disease-free survival at 3 years (ITT analysis)* in the Overall population

*  Median  follow-up  at  44.2  months  (all  patients  followed  for  at  least  3  years).


The study demonstrated a significant global advantage in 3 years disease-free survival for the oxaliplatin and 5-FU/FA combination (FOLVOX4) over 5-FU/FA alone (LV5FU2).


EFC3313: Disease-free survival at 3 years (ITT analysis)* according to stage of disease

*  Median  follow-up  at  44.2  months  (all  patients  followed  for  at  least  3  years).


Overall survival (ITT analysis)

At time of the analysis of the 3-year disease free survival, which was the primary endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in mortality risk of 10% in favour of FOLVOX4 not reaching statistical significance (hazard ratio = 0.90).

The figures were 92.2% versus 92.4% in the stage II (Duke’s B2) sub-population (hazard  ratio  = 1.01)  and  80.4% versus  78.1  in  the  stage  III  (Duke’s  C)  sub- population (hazard ratio = 0.87), for FOLFOX4 and LS5FU2, respectively.

 

Pharmacokinetic properties

The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and  inactive  platinum  species, following  a  two-hour  infusion  of  oxaliplatin  at  130 mg/m² every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m² every two weeks for 1 to 3 cycles are as follows:

Mean  values  of  AUC  0-48  and  calculated  on  cycle  3  (85  mg/m²)  or  on  cycle  5 (130  mg/m²).

Mean values of AUC, V, CL, and CLR 0-48 calculated on cycle 1.

Values of Cfinal, Cmax, AUC, AUC0-48, and CL calculated using non compartmental analysis.

T½  α,  T½  β,  and  T½  γ    calculated  using  non  compartmental  analysis  (cycles  1-3 combined).

At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half lives in these matrices that are dose to the natural turnover of red blood cells and serum albumin. No accumulation as observed in plasma ultrafiltrate following 85 mg/m² every two weeks or 130 mg/m² every three weeks and steady state was attained  by  cycle  one  in  this  matrix.  Inter-  and  intra-subject  variability  is  generally low.

In vitro, metabolites result from non-enzymatic degradation and there is no evidence of cytochrome P-450-mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2h-infusion. Several cytotoxic metabolites including the monochloro-, dichloro-, and diaquo-DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points.

Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration.

By day 5, approximately 54% of the total dose was recovered in the urine and < 3% in the faeces. A significant decrease in clearance from 17.6 ± 2.18 l/h to 9.95

± 1.91 l/h in renal impairment was observed together with a statistically significant decrease in distribution volume from 330 ± 40.9 to 241 ± 36.1 l. The effect of severe renal impairment on platinum clearance has not been evaluated.

 

PRECLINICAL SAFETY DATA

The  target  organs  identified  in  species  used  during  preclinical  studies  (mice,  rats, dogs, and/or monkeys) following single doses and repeated doses included the bone marrow, the gastrointestinal system, the kidney, testes, the nervous system, and the heart. The toxicities in target organs observed in animals are concistent with those observed with other platinum agents and other cytotoxic drugs interacting with DNA and used in the treatment of human cancer, with the exception of the effects produced on the hearth. Effects on the heart were only observed in the dog and included electrophysiological abnormalities with lethal ventricular fibrillation.

Cardiotoxicity was considered as specific to the dog not only because it was observed in the dog, but also because doses similar to those producing lethal cardiotoxicity in dogs  (150  mg/m²)  were  well-tolerated  in man. Preclinical  studies  using  rat  sensory neurons suggest the acute neurosensory symptoms related to Oxaliplatin may be linked to an interaction with voltage-gated Na+ channels. Oxaliplatin is mutagenic and clastogenic in mammalian have been performed concerning its carcinogenic potential. Oxaliplatin is considered as probably being carcinogenic.

 

PHARMACEUTICAL PARTICULARS

List of excipients

Water for Injection

 

Incompatibilities

This medicinal product should not be mixed with other medicinal products, apart from those indicated in section 6.6.

·      DO  NOT  use  in  association  with  alkaline  medicinal  products  or  media  (in  particular 5-fluorouracil,  base  solutions,  trometamol  and  folinic  acid  products  containing trometamol as an excipient).

·      DO NOT dilute for infusion with saline solution.

·      DO NOT mix with other medicinal products in the same infusion bag or infusion line (see Section 6.6 for instructions concerning simultaneous administration with folinic acid).

·      DO NOT see injection equipment containing aluminium.

 

Shelf life

2 years

After dilution in 5% glucose solution, the physicochemical stability has been demonstrated for 24 hours at 2°C to 8°C or 6 hours at 25°C.

However from a microbiological point of view, the product should be used immediately. If not used immediately, the conditions and duration of storage after dilution and prior to use are the sole responsibility of the user, but the duration of storage should not exceed 24 hours at 2°C to 8°C unless dilution was performed under controlled, validated and aseptic conditions.

 

Special precautions for storage

Store the vial in the outer packaging, protected from light.

Do not freeze.

 

Nature and contents of container

10 ml or 20 ml vial (Type I colourless glass) with a stopper (bromobutyl)

 

Instructions for Handling

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and his surroundings.


Special precaution for administration

- NEVER use injection material containing aluminium.

- NEVER administer undiluted.

- NEVER dilute the product with saline solution.

- NEVER mix with any other medicines in the same infusion bag, or administer simultaneously  by  the  same  infusion  line  (particularly  5-fluorouracil,  base  solutions, trometamol and folinic acid products containing trometamol as an excipient). Oxaliplatin may be co-administered with folinic acid using a Y-line placed immediately before the site of injection. The medicine must not be combined in the same infusion bag. Folinic acid must be diluted with isotonic infusion solutions such as 5% glucose solution but NEVER with saline or alkaline solutions. Flush the infusion line after administering oxaliplatin.

- USE ONLY the recommended solvent (see below).


Concentrate for solution for infusion

Inspect visually prior to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused should be discarded.


Dilution prior to infusion

Withdraw the required amount of concentrate for solution from the vial and then dilute with 250 to 500 ml of 5% glucose solution to give an oxaliplatin concentration not less than 0.2 mg/ml.

Administer by intravenous infusion

Inspect visually prior to use. Only clear solutions without particles should be used. The medicinal product is for single use only. Any unused should be discarded.

NEVER use sodium chloride solution for dilution.

Infusion

The administration of oxaliplatin does not require prehydration.

Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give an oxaliplatin concentration not less than 0.2 mg/ml must be infused either by peripheral vein or central venous line over 2 to 6 hours. When oxaliplatin is administered with 5- fluorouracil,  the  oxaliplatin  infusion  should  precede  that  of  5-fluorouracil.

Waste Disposal

Any unused product, as well as all materials used for dilution and administration, must be destroyed in compliance with hospital standard procedures applicable to cytotoxic agents with due regard to current laws related to the disposal of hazardous waste.


NATURE AND CONTENTS OF CONTAINER

ELOXATIN  50  mg  vials  10  ml  (colourless  glass),  box  of  1 Reg. No. DKI1359202649A1

ELOXATIN  100  mg  vials  20  ml  (colourless  glass),  box  of  1 Reg. No. DKI1359202649A1

 

HARUS DENGAN RESEP DOKTER

Manufactured by:

Sanofi-Aventis Deutschland GmbH,  Frankfurt  (Main)  -  Germany


Registered by:

PT Aventis Pharma, Jakarta – Indonesia

 

Date of text revision:

As on approval date


This information is intended for Health Care Professional only. See local product information for full details information